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United States Patent |
5,250,535
|
Verheyden
,   et al.
|
October 5, 1993
|
Substituted 9-(1 or 3-monoacyloxy or 1,3-diacyloxy-2-propoxymethyl)
purines as antiviral agent
Abstract
Compounds useful as antiviral agents are defined by the following formula:
##STR1##
and the pharmaceutically acceptable acid addition salts thereof wherein
R.sup.1 is hydrogen or --C(O)R.sup.7 wherein R.sup.7 is hydrogen, alkyl of
one to nineteen carbon atoms, hydroxyalkyl of one to eight carbon atoms,
alkoxyalkyl of two to nine carbon atoms, alkenyl of two to nineteen carbon
atoms, phenyl, 1-adamantyl or 2-carboxyethyl and the pharmaceutically
acceptable alkali metal salts thereof;
R.sup.2 is --C(O)R.sup.7 wherein R.sup.7 is as defined above;
R.sup.3 is hydrogen, halo, thio, lower alkylthio of one to six carbon
atoms, azido, NR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are
independently hydrogen or lower alkyl of one to six carbon atoms or
--NHC(O)R.sup.8 wherein R.sup.8 is hydrogen, alkyl of one to nineteen
carbon atoms or 1-adamantyl; and
(a) R.sup.6 is hydrogen, halo, lower alkoxy of one to six carbon atoms,
azido, thio, lower alkylthio of one to six carbon atoms, --NR.sup.9
R.sup.10 wherein R.sup.9 and R.sup.10 are as defined above or
--NHC(O)R.sup.8 wherein R.sup.8 is as defined above and R.sup.4 together
with R.sup.5 is a bond; or
(b) R.sup.5 together with R.sup.6 is a keto group and R.sup.4 is hydrogen.
Inventors:
|
Verheyden; Julien P. H. (Los Altos, CA);
Martin; John C. (Redwood City, CA)
|
Assignee:
|
Syntex Inc. (Palo Alto, CA)
|
Appl. No.:
|
451262 |
Filed:
|
December 22, 1982 |
Current U.S. Class: |
514/263.38; 514/263.4; 544/276; 544/277 |
Intern'l Class: |
C07D 473/18; A61K 031/52 |
Field of Search: |
424/253
544/277,276
514/261,262
|
References Cited
U.S. Patent Documents
4199574 | Apr., 1980 | Schaeffer | 544/277.
|
4323573 | Apr., 1982 | Shaeffer | 544/277.
|
4347360 | Aug., 1982 | Ogilvie | 544/276.
|
4816447 | Mar., 1989 | Ashton et al. | 544/277.
|
Foreign Patent Documents |
0049072 | Apr., 1982 | EP.
| |
2104070A | Mar., 1983 | GB.
| |
Primary Examiner: Rizzo; Nicholas S.
Attorney, Agent or Firm: Wong; James J., Lowin; David A., Moran; Tom M.
Parent Case Text
This is a continuation-in-part of U.S. Ser. No. 344,703 filed Feb. 1, 1982
now abandoned.
Claims
What is claimed is:
1. A compound of the formula
##STR6##
of a pharmaceutically acceptable acid addition salt thereof wherein
R.sup.1 is hydrogen or --C(O)R.sup.7 wherein R.sup.7 is hydrogen, alkyl of
one to nineteen carbon atoms, hydroxyalkyl of one to eight carbon atoms,
alkoxyalkyl of two to nine carbon atoms, alkenyl of two to nineteen carbon
atoms, phenyl, or 2-carboxyethyl and the pharmaceutically acceptable
alkali metal salts thereof;
R.sup.2 is --C(O)R.sup.7 wherein R.sup.7 is as defined above;
R.sup.3 is amino; and
(a) R.sup.6 is hydrogen, thio, or amino and R.sup.4 together with R.sup.5
is a bond; or
(b) R.sup.5 together with R.sup.6 is a keto group and R.sup.4 is hydrogen.
2. A compound of claim 1 of the formula
##STR7##
wherein R.sup.1 and R.sup.2 are as defined in claim 1.
3. A compound of claim 2 wherein R.sup.1 and R.sup.2 are independently
--C(O)R.sup.7 wherein R.sup.7 is as defined in claim 1.
4. A compound of claim 3 wherein R.sup.7 is methyl which is
9-(1,3-diacetyloxy-2-propoxymethyl)guanine.
5. A compound of claim 3 wherein R.sup.7 is ethyl which is
9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine.
6. A compound of claim 3 wherein R.sup.7 is n-propyl which is
9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine.
7. A compound of claim 3 wherein R.sup.7 is n-butyl which is
9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine.
8. A compound of claim 3 wherein R.sup.7 is 2-methyl-2-propyl which is
9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine.
9. A compound of claim 3 wherein R.sup.7 is n-pentyl which is
9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine.
10. A compound of claim 3 wherein R.sup.7 is 3-methyl-1-butyl which is
9-(1,3-di-(4-methylpentanoyloxy)-2-propoxymethyl)guanine.
11. A compound of claim 3 wherein R.sup.7 is methoxymethyl which is
9-[1,3-di-(methoxyacetyloxy)-2-propoxymethyl]guanine.
12. A compound of claim 3 wherein R.sup.7 is phenyl which is
9-(1,3-dibenzoyloxy-2-propoxymethyl)guanine.
13. A compound of claim 3 wherein R.sup.7 is n-heptyl which is
9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine.
14. A compound of claim 3 wherein R.sup.7 is n-nonyl which is
9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine.
15. A compound of claim 3 wherein R.sup.7 is n-undecyl which is
9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine.
16. A compound of claim 3 wherein R.sup.7 is n-tridecyl which is
9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine.
17. A compound of claim 3 wherein R.sup.7 is n-pentadecyl which is
9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine.
18. Compound of claim 3 wherein R.sup.7 is 2-carboxyethyl which is
9-[1,3-di-(3-carboxypropanoyloxy-2-propoxymethyl]guanine and the
pharmaceutically acceptable alkali metal salts thereof.
19. A compound of claim 2 wherein R.sup.1 is hydrogen and R.sup.2 is
--C(O)R.sup.7 wherein R.sup.7 is as defined in claim 1.
20. A compound of claim 19 wherein R.sup.7 is methyl which is
9-(1-acetyloxy-3-hydroxy-2-propoxylmethyl)guanine.
21. A compound of claim 19 wherein R.sup.7 is 2-methyl-2-propy which is
9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine.
22. A compound of claim 19 wherein R.sup.7 is methoxymethyl which is
9-(1-methoxyacetyloxy-3-hydroxy-2-propoxymethyl)guanine.
23. A compound of claim 19 wherein R.sup.7 is n-heptyl which is
9-(1-n-octanoyloxy-3-hydroxy-2-propoxymethyl)guanine.
24. A compound of claim 19 wherein R.sup.7 is n-pentadecyl which is
9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine.
25. A compound of claim 19 wherein R.sup.7 is 2-carboxyethyl which is
9-[1-(3-carboxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine and the
pharmaceutically acceptable alkali metal salts thereof.
26. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and a compound of the formula
##STR8##
or a pharmaceutically acceptable salt thereof wherein R.sup.1 is hydrogen
or --C(O)R.sup.7 wherein R.sup.7 is hydrogen, alkyl of one to nineteen
carbon atoms, hydroxyalkyl of one to eight carbon atoms, alkoxyalkyl of
two to nine carbon atoms, alkenyl of two to nineteen carbon atoms, phenyl,
or 2-carboxyethyl and the pharmaceutically acceptable alkali metal salts
thereof;
R.sup.2 is --C(O)R.sup.7 wherein R.sup.7 is as defined above;
R.sup.3 is amino, alkyl of one to nineteen carbon atoms or 1-adamantyl; and
(a) R.sup.6 is hydrogen, thio, or amino and R.sup.4 together with R.sup.5
is a bond; or
(b) R.sup.5 together with R.sup.6 is a keto group and R.sup.4 is hydrogen.
27. A pharmaceutical composition of claim 26 which comprises a
pharmaceutically acceptable carrier and a compound of the formula
##STR9##
wherein R.sup.1 and R.sup.2 are as defined in claim 26.
28. A pharmaceutical composition of claim 27 wherein R.sup.1 and R.sup.2
are independently --C(O)R.sup.7 wherein R.sup.7 is as defined in claim 26.
29. A pharmaceutical composition of claim 28 wherein R.sup.7 is methyl.
30. A pharmaceutical composition of claim 28 wherein R.sup.7 is ethyl.
31. A method of treating viral infection in a warm blooded or a cold
blooded animal having a viral infection which comprises administering an
effective amount of a compound of the formula
##STR10##
or a pharmaceutically acceptable salt thereof wherein R.sup.1 is hydrogen
or --C(O)R.sup.7 wherein R.sup.7 is hydrogen, alkyl of one to nineteen
carbon atoms, hydroxyalkyl of one to eight carbon atoms, alkoxyalkyl of
two to nine carbon atoms, alkenyl of two to nineteen carbon atoms, phenyl,
or 2-carboxyethyl and the pharmaceutically acceptable alkali metal salts
thereof;
R.sup.2 is --C(O)R.sup.7 wherein R.sup.7 is as defined above;
R.sup.3 is amino; and
(a) R.sup.6 is hydrogen, thio, or amino and R.sup.4 together with R.sup.5
is a bond; and
(b) R.sup.5 together with R.sup.6 is a keto group and R.sup.4 is hydrogen.
32. A method according to claim 31 wherein the virus is Herpes Simplex
virus I.
33. A method according to claim 31 wherein the virus is Herpes Simplex
virus II.
34. A method according to claim 31 wherein the virus is cytomegalovirus.
35. A method according to claim 31 wherein the virus is Epstein-Barr virus.
36. A method according to claim 31 wherein the virus is voricella Zoster
virus.
37. A method according to claim 31 wherein the virus is viral hepatitis.
38. A method of claim 31 which comprises administering an effective amount
of a compound of the formula
##STR11##
wherein R.sup.1 and R.sup.2 are as defined in claim 31.
39. A method according to claim 38 wherein the virus is Herpes Simplex
virus I.
40. A method according to claim 38 wherein the virus is Herpes Simplex
virus II.
41. A method according to claim 38 wherein the virus is cytomegalovirus.
42. A method according to claim 38 wherein the virus is Epstein-Barr virus.
43. A method according to claim 38 wherein the virus is voricella Zoster
virus.
44. A method according to claim 38 wherein the virus is viral hepatitis.
45. A method of claim 38 wherein R.sup.1 and R.sup.2 are independently
--C(O)R.sup.7 wherein R.sup.7 is as defined in claim 31.
46. A method of claim 45 wherein R.sup.7 is methyl.
47. A method of claim 45 wherein R.sup.7 is ethyl.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to substituted 9-(1 or 3-monoacyloxy or
1,3-diacyloxy-2-propoxymethyl)purines and pharmaceutically acceptable acid
addition salts thereof which are useful as antiviral agents. The invention
also relates to a pharmaceutical composition containing the above
compounds in combination with a suitable non-toxic carrier, the
composition being useful in combatting viral infections. The invention
also relates to a process for preparing the compounds of the invention.
2. Related Disclosure
Viral infections are widespread and result in a wide variety of symptoms.
Some viral infections are easily overcome by the body's defense mechanism,
but when this defense mechanism is impaired these infections can lead to
permanent damage, e.g., blindness, and even to death. One such family of
viruses which may cause serious infections is the herpes virus group.
The drugs presently used to treat viral infections are ineffective in many
cases or, if effective, are needed in large and/or continuous dosages
which produce serious side-effects and/or toxicity. Therefore there is a
need for an effective antiviral agent which is effective at lower dosages
than the presently available drugs, thus diminishing the chance of
possible side-effects and toxicity.
U.S. Pat. No. 4,199,574 discloses compounds represented by the following
generic formula:
##STR2##
wherein X is sulphur or oxygen, R.sup.1 is hydrogen, halogen, hydroxy,
alkoxy, azide, thio, alkylthio, amino, alkylamino or dialkylamino; R.sup.2
is hydrogen, halogen, alkylthio, acylamino, amino or azide; R.sup.3 is
hydrogen, straight or branch chain or cyclic alkyl, hydroxyalkyl,
benzyloxyalkyl or phenyl; R.sup.4 is hydrogen, hydroxy or alkyl; R.sup.5
is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy,
benzoyloxymethyl, sulphamoyloxy, phosphate, carboxypropiamyloxy, straight
chain or cyclic acyloxy having from 1 to 8 carbon atoms e.g., acetoxy or
substituted carbamoyl group of formula NHCO-Z wherein Z is alkyl, aryl or
aralkyl optionally substituted by one or more of sulphonyl, amino,
carbamoyl or halogen; R.sup.6 is hydrogen or alkyl, provided that when X
is oxygen and R.sup.2, R.sup.3, R.sup.4, and R.sup.6 are hydrogen, R.sup.1
is not amino or methylamino when R.sup.5 is hydrogen or hydroxy, or a salt
thereof.
The class of compounds represented by the above formula and the
pharmaceutically acceptable acid addition salts thereof are described to
exhibit antiviral activity. See also Tetrahedron Letters, 21, 327-30
(1980), U.S. Pat. No. 4,294,831 and U.S. Pat. No. 4,347,360.
SUMMARY OF THE INVENTION
It has now been discovered that substituted 9-(1 or 3-monoacyloxy- or
1,3-diacyloxy-2-propoxymethyl)purines and the salts thereof are
particularly active antiviral agents.
The first aspect of the present invention is the compound of the following
formula:
##STR3##
and the pharmaceutically acceptable acid addition salts thereof wherein
R.sup.1 is hydrogen or --C(O)R.sup.7 wherein R.sup.7 is hydrogen, alkyl of
one to nineteen carbon atoms, hydroxyalkyl of one to eight carbon atoms,
alkoxyalkyl of two to nine carbon atoms, alkenyl of two to nineteen carbon
atoms, phenyl, 1-adamantyl or 2-carboxyethyl and the pharmaceutically
acceptable alkali metal salts thereof;
R.sup.2 is --C(O)R.sup.7 wherein R.sup.7 is as defined above;
R.sup.3 is hydrogen, halo, thio, lower alkylthio of one to six carbon
atoms, azido, NR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are
independently hydrogen or lower alkyl of one to six carbon atoms or
--NHC(O)R.sup.8 wherein R.sup.8 is hydrogen, alkyl of one to nineteen
carbon atoms or 1-adamantyl; and
(a) R.sup.6 is hydrogen, halo, lower alkoxy of one to six carbon atoms,
azido, thio, lower alkylthio of one to six carbon atoms, --NR.sup.9
R.sup.10 wherein R.sup.9 and R.sup.10 are as defined above or
--NHC(O)R.sup.8 wherein R.sup.8 is as defined above and R.sup.4 together
with R.sup.5 is a bond; or
(b) R.sup.5 together with R.sup.6 is a keto group and R.sup.4 is hydrogen.
Another aspect of the invention relates to pharmaceutical compositions for
antiviral use comprising the compounds of the instant invention and a
suitable carrier.
A further aspect of the invention is a method of treating viral infections
consisting of administering a compound of the present invention or a
composition containing same.
Another aspect of the invention are the novel compounds of formulas (IXa)
and (XIV)(infra) wherein A is hydrogen which are useful as intermediates
and as antiviral agents.
Yet another aspect of the invention is a process for preparing the
compounds of formula (I) which comprises esterifying a compound of formula
(X) or (XIV) infra.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENT
As used in the specification and appended claims, unless specified to the
contrary, the following terms have the meaning indicated.
The term "alkyl" refers to a straight or branched chain monovalent
substituent consisting solely of carbon and hydrogen, containing no
unsaturation and having one to nineteen carbon atoms. Examples of alkyl
are methyl, n-butyl, 2-methyl-2-propyl, n-octyl, n-decyl, n-tetradecyl and
n-nonadecyl. The term "lower alkyl" refers to alkyl groups as defined
above but containing one to six carbon atoms. The term "alkenyl" refers to
a straight or branched chain monovalent substituent consisting solely of
carbon and hydrogen, containing one or more double bonds and having two to
nineteen carbon atoms. Examples of "alkenyl" are propenyl, pentenyl,
heptenyl, dodecenyl, dodecadienyl, pentadecenyl and pentadecadienyl. The
term "1-adamantyl" refers to the following ring structure.
##STR4##
"Lower alkoxy" refers to "lower alkyl-O-" wherein "lower alkyl" is as
defined above. Examples of "lower alkoxy" are methoxy, ethoxy, i-butoxy
and n-hexyloxy. The term "alkoxyalkyl" refers to alkyl-O-alkylene wherein
alkyl is as defined above and alkylene is a divalent alkyl group. Examples
of "alkoxyalkyl" are methoxymethyl, i-propoxymethyl, n-octanyloxymethyl
and ethoxypropyl. The term "lower alkylthio" refers to "lower alkyl-S-"
wherein "lower alkyl" is as defined above. Examples of "lower alkylthio"
are methylthio, n-propylthio and n-pentylthio. "Thio" refers to --SH.
"Amino" refers to --NH.sub.2. "Azido" refers to N.sub.3. "Halo" refers to
fluoro, chloro and bromo. "2-Carboxyethyl" refers to HOOCCH.sub.2 CH.sub.2
--.
"Pharmaceutically acceptable acid addition salts" refers to those salts
which possess the biological effectiveness and properties of the free
compound and which are not biologically or otherwise undesirable. Suitable
acids for salt formation are inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid and the like, and organic
acids such as trifluoroacetic acid, menthanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid and the like.
"Pharmaceutically acceptable alkali metal salts" refers to the metal salts
of the free carboxy group of the carboxyethyl group. Examples of alkali
metals are sodium and potassium.
Compounds of formula (I) wherein R.sup.1 is hydrogen and R.sup.2 is
C(O)R.sup.7 contain an assymetric carbon atom. Accordingly, these
compounds may be prepared in either optically active form, or as a racemic
mixture. Unless otherwise specified, the monoesters of formula (I)
described herein are all in the racemic form. However, the scope of the
subject invention is not to be considered limited to the racemic form, but
to encompass the individual optical isomers of the monoesters of formula
(I).
It is to be understood that the definition of R.sup.5 together with R.sup.6
as keto includes the tautomeric hydroxy form but for convenience the keto
form will be used to represent both tautomeric forms.
A preferred group of compounds of formula (I) is that wherein R.sup.3 is
amino, R.sup.4 is hydrogen and R.sup.5 together with R.sup.6 is keto
(compounds of formula (Ia) infra). Another preferred group of compounds of
formula (I) is that wherein R.sup.3 is amino and R.sup.6 is hydrogen, thio
or NH.sub.2 and R.sup.4 together with R.sup.5 is a bond. A preferred
subgroup within these groups is that wherein R.sup.1 and R.sup.2 are both
--C(O)R.sup.7. A more preferred subgroup is that wherein R.sup.7 is alkyl
of one to five carbon atoms with R.sup.7 being methyl or ethyl being most
preferred. Another preferred subgroup within these groups is that wherein
R.sup.1 is hydrogen and R.sup.2 is --C(O)R.sup.7. A more preferred
subgroup within this subgroup is that wherein R.sup.7 is alkyl of one to
five carbon atoms with R.sup.7 being methyl or ethyl being the most
preferred.
UTILITY AND ADMINISTRATION
The subject compound of formula (I) and the pharmaceutically acceptable
salts thereof exhibit potent antiviral activity when administered to warm
blooded and cold blooded animals, particularly mammals, birds, and fish,
but most particularly humans. For example, the compound of the present
invention exhibits excellent activity against Herpes Simplex virus I and
II and related viruses such as cytomegalovirus, Epstein-Barr virus and
varicella Zoster virus as well as viral hepatitis such as hepatitis B.
Compounds of formula (I) wherein R.sup.1 and R.sup.2 are --C(O)R.sup.7
wherein R.sup.7 is ethyl, i.e., the dipropanoate ester exhibits properties
which make it particularly suitable for the treatment of viral infections.
This ester is more soluble in aqueous solutions than would be expected
from the solubility of the adjacent homologs, thus making the dipropanoate
ester particularly suitable for parenteral administration. Further, the
dipropanoate is more bioavailable.
Pharmaceutical compositions, both veterinary and human, containing the
subject compound appropriate for antiviral use are prepared by methods and
contain excipients which are well known in the art. A generally recognized
compendium of such methods and ingredients is Remington's Pharmaceutical
Sciences by E. W. Martin, (Mark Publ. Co., 15th Ed., 1975). Liposomes may
also be employed as pharmaceutical compositions for the compounds of
formula (I), using methods known in the art [for example, as described in
Szoka, F. Jr., et al, Ann. Rev. Biophys. Bioeng. 9:467-508 (1980),
Schullery, S. E. et al, Biochemistry 19:3919-23 (1980) and Gregoriadin, G.
et al, "Liposomes in Biological Systems:", John Wiley and Sons (1980)].
The compound of the invention may be administered parenterally (for
example, by intraveneous, subcutaneous, intraperitoneal or intramuscular
injection), orally, topically, rectally or intranasally.
The compositions are administered orally or parenterally at dose levels,
calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to
30 mg/kg of mammal body weight, and are used in man in a unit dosage form,
administered one to five times daily in the amount of 1 to 500 mg per unit
dose. For oral administration, fine powders or granules may contain
diluting, dispersing and/or surface active agents, and may be presented in
a draught, in water or in a syrup; in capsules or sachets in the dry state
or in a non-aqueous solution or suspension, wherein suspending agents may
be included; in tablets, wherein binders and lubricants may be included;
in a suspension in water or a syrup; or in an aerosol. Where desirable or
necessary, flavoring, preserving, suspending, thickening or emulsifying
agents may be included. Tablets and granules are preferred, and these may
be coated. The amount of compound of formula (I) in the formulation may
vary from 0.1 percent weight (%w) to 99%w or more of the compound based on
the total formulation and about 1%w to 99.9%w excipient. Preferably the
compound is present at a level of 10%-95%w.
For parenteral administration or for administration as drops, as for eye
infections, the compounds may be presented in aqueous solution in a
concentration of from about 0.1 to 10%, more preferably about 0.1 to 7%.
The solution may contain antioxidants, buffers, and other suitable
additives.
Alternatively for infections of the eye, or other external tissues, e.g.
mouth and skin, the compositions are preferably applied to the infected
part of the body of the patient topically as an ointment, cream, aerosol
or powder, preferably in an ointment or cream. The compounds may be
presented in an ointment, for instance with a water soluble ointment base,
or in a cream, for instance with an oil in water cream base, in a
concentration of from about 0.01 to 10%; preferably 0.1 to 7%, most
preferably about 3.0% w/v. Additionally, viral infections may be treated
by use of a sustained release drug delivery system as is described in U.S.
Pat. No. 4,217,898.
For aerosol administration, the active ingredient is preferably supplied in
finely divided form along with a surfactant and a propellant. Typical
percentages of active ingredients are 0.01 to 20% by weight, preferably
0.04 to 1.0%.
Surfactants must, of course, be non-toxic, and preferably soluble in the
propellant. Representative of such agents are the esters or partial esters
of fatty acids containing from 6 to 22 carbon atoms, such as caproic,
octanoic, lauric, palmitic, stearic, linoleic, linolenic, olestearic and
oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride
such as, for example, ethylene glycol, glycerol, erythritol, arabitol,
mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the
sorbitan esters sold under the trademark "Spans") and the polyoxyethylene
and polyoxypropylene derivatives of these esters. Mixed esters, such as
mixed or natural glycerides may be employed. The preferred surface-active
agents are the oleates or sorbitan, e.g., those sold under the trademarks
"Arlacel C" (Sorbitan sesquioleate), "Span 80" (sorbitan monooleate) and
"Span 85" (sorbitan trioleate). The surfactant may constitute 0.1-20% by
weight of the composition, preferably 0.25-5%.
The balance of the composition is ordinarily propellant. Liquefied
propellants are typically gases at ambient conditions, and are condensed
under pressure. Among suitable liquefied propellants are the lower alkanes
containing up to five carbons, such as butane and propane; and preferably
fluorinated or fluorochlorinated alkanes, such as are sold under the
trademark "Freon." Mixtures of the above may also be employed.
In producing the aerosol, a container equipped with a suitable valve is
filled with the appropriate propellant, containing the finely divided
active ingredient and surfactant. The ingredients are thus maintained at
an elevated pressure until released by action of the valve.
The compounds of the present invention or compositions containing same are
also useful in treating non-human mammals, birds, e.g., chickens and
turkeys, and cold-blooded animals, e.g., fish. For example, the compounds
of the present invention and compositions containing same exhibit
antiviral activity against the following non-human viruses:
Sciruid herpesvirus 1
Cavlid herpesvirus 1
Lagomorph herpesvirus 1
Phasianid herpesvirus 1
Phasianid herpesvirus 2 (Marek's disease)
Turkey herpesvirus 1
Anatid herpesvirus 1
Catfish herpesvirus 1
Equid herpesvirus 3
Bovid herpesvirus 1
Bovid herpesvirus 2
Bovid herpesvirus 3
Bovid herpesvirus 4
Pig herpesvirus 1
Pig herpesvirus 2
Murid herpesvirus 1
Cebid herpesvirus 1
Cebid herpesvirus 2
Tupaiid herpesvirus 1
Canine herpesvirus 1
Feline herpesvirus 1
Equid herpesvirus 1
Equid herpesvirus 2
Avian viral diseases such as Marek's disease and the like are prevented
and/or treated by compounds of the present invention by methods well-known
in the veterinary art such as by injecting the birds with the composition
containing the compound, or by adding the compound of the instant
invention to feed or drinking water.
Fish which are in a confined area such as a pool, aquarium or holding tank
may also be treated for viral infections such as herpeslike viruses, e.g.,
channel catfish virus (CCV), herpes-virus salomones, Nerka virus and the
like by adding the compound directly to the water of the pool, aquarium or
holding tank or by incorporating the compounds into the feed.
The exact regimen for administration of the compounds and compositions
disclosed herein will necessarily be dependent upon the needs of the
individual subject being treated, the type of treatment and, of course,
the judgement of the attending practitioner.
PREPARATION
The compounds of formula (I) may be prepared from compounds of formula (X)
(infra) and compounds of formula (XIV) wherein A is hydrogen (infra) which
compounds are prepared by Reaction Sequence Ib. Intermediate of formula
(V), which is used in Reaction Sequence Ib, is prepared by Reaction
Sequence Ia.
##STR5##
wherein A is hydrogen or acetyl and R.sup.3 and R.sup.6 are defined in the
following table:
______________________________________
R.sup.3 R.sup.6
______________________________________
a) NH.sub.2 OR
b) NH.sub.2 SH
c) N.sub.3 N.sub.3
d) NH.sub.2 NH.sub.2
e) Cl NH.sub.2
f) N.sub.3 NH.sub.2
g) NH.sub.2 H
h) H NH.sub.2
i) H SH
j) SH NH.sub.2
______________________________________
In Reaction Sequence Ia, the compound of formula (III) is prepared by
adding epichlorohydrin (II) dropwise to a solution of an alkali metal
salt, preferably the sodium salt, of optionally substituted benzyl alcohol
in a solvent such as dimethylformamide, dimethylacetamide,
hexamethylphosphoramide, dimethylsulfoxide, sulfolane, tetrahydrofuran,
and dioxane at a temperature of about 0.degree. C. to 100.degree. C.,
preferably at about 15.degree. C. to 40.degree. C. The reaction mixture is
stirred for about 10 hours to 24 hours, preferably for about 12 hours to
18 hours at a temperature of about 0.degree. C. to 100.degree. C.,
preferably from about 20.degree. C. to 50.degree. C.
Compound of formula (III) is chloromethylated to compound of formula (IV)
by bubbling dry hydrogen chloride gas in a solution of the compound and
paraformaldehyde dissolved in a halogenated hydrocarbon solvent such as
dichloroethane, chloroform, dichloromethane, or 1,1,2-trichloroethane
cooled to a temperature of about 0.degree. C. to 25.degree. C., preferably
at a temperature of about 0.degree. C. The hydrogen chloride gas is added
over 30 minutes to 3 hours, preferably over 1 hour to 2 hours until the
paraformaldehyde dissolves. The solution is held at a temperature from
about 0.degree. C. to 10.degree. C. for about 12 hours to 48 hours,
preferably from about 0.degree. to 5.degree. C. for about 16 hours to 24
hours.
Compound of formula (V) is prepared by reacting an alkali metal acetate
such as sodium acetate with compound of formula (IV) dissolved in a
solvent such as dimethylformamide, tetrahydrofuran, dimethylacetamide,
hexamethylphosphoramide, dimethylsulfoxide, sulfolane, and dioxane at a
temperature of about 0.degree. C. to 45.degree. C., preferably from about
0.degree. C. to 25.degree. C. The solution is stirred from about 5 to
about 24 hours, preferably from about 10 hours to about 18 hours at a
temperature of about 10.degree. C. to about 30.degree. C., preferably at a
temperature of about 15.degree. C. to 25.degree. C.
In Reaction Sequence Ib, compound of formula (VII) is prepared by heating
guanine (VI) with acetic anhydride, neat, at reflux for about 10 to 24
hours, preferably for about 12 to 18 hours.
N.sup.2,9-Diacetylguanine of formula (VII) is reacted with compound of
formula (V) to form compound of formula (VIII) neat or in a solvent such
as dioxane, sulfolane and the like in the presence of a catalytic amount
of an acid such as bis(p-nitrophenyl)phosphate, toluenesulfonic acid,
methylphosphonic acid or dichloroacetic acid, preferably
bis(p-nitrophenyl)phosphate at a temperature of about 75.degree. C. to
200.degree. C., preferably at about 110.degree. C. to 180.degree. C. The
reaction is generally carried out using 0.8 moles to 1.2 moles of compound
of formula (V) to one mole of compound of formula (VII).
The benzyl protecting groups are removed from compound of formula (VIII) by
catalytic hydrogenation to form compound of formula (IX). A catalyst such
as palladium on carbon in a slurry is added to a solution of compound of
formula (VIII) dissolved in a solvent such as aqueous methanol. Hydrogen
is added to the solution at a pressure of 15 psi to 200 psi, preferably at
a pressure of 30 psi to 80 psi.
Compound of formula (X) is prepared by deacetylating compound of formula
(IX) with a base such as ammonia dissolved in an alcohol such as methanol.
A solution of compound of formula (IX) and the base is stirred for about 5
hours to 36 hours, preferably for about 10 hours to 24 hours at a
temperature of about 10.degree. C. to 30.degree. C., preferably at a
temperature of about 15.degree. C. to 25.degree. C.
Compound of formula (X) may be esterified to the diacetate of formula (XI)
by reacting compound of formula (X) with excess acetic anhydride, either
neat or in a solvent such as dimethylformamide, dimethylacetamide and the
like at room temperature for two to three days.
Compound of formula (XII) may be prepared by reacting compound of formula
(XI) with phosphorus oxychloride according to the method described in J.
Org. Chem. 28:945, 1963. Compound of formula (XI) is added to a solution
of phosphorus oxychloride in N,N-diethylaniline at room temperature. The
suspension is heated at reflux for 2 to 30 minutes, preferably from 2 to 5
minutes. The excess phosphorus oxychloride is removed and the product
recovered by conventional means such as extraction with an organic solvent
followed by chromatography.
Compound of formula (XII) may be further chlorinated by forming the diazo
salt with sodium nitrite in hydrochloric acid as described in J. Org.
Chem. 31:3258, 1966. To compound of formula (XII) in aqueous hydrochloric
acid is added sodium nitrite in water at 0.degree. to 5.degree. C. The
solution is diluted with water and the excess hydrochloric acid is
neutralized with aqueous ammonia and compound of formula (XIII) is
recovered by methods well known in the art such as extraction with an
organic solvent followed by chromatography.
Compounds of formula (XIV) may be prepared from compounds of formulas (XII)
and (XIII) by methods well known in the art. See, for example,
"Heterocyclic Compounds--Fused Pyrimidines Part II Purines, Ed. D. J.
Brown (1971) Wiley-Interscience" and U.S. Pat. No. 4,199,574 which patent
is incorporated herein by reference. See preceding table for compounds of
formula (XIV)a-j.
Compound of formula (XIVb) wherein A is hydrogen may be prepared by
reacting a compound of formula (XII) with thiourea dissolved in a solvent
such as isopropanol with heating at reflux for one to two hours. The
thiourea adduct which forms is broken down with an alkali such as aqueous
ammonia yielding the thio compound. The reaction also leads to the
hydrolysis of the ester groups.
Compounds of formula (XIVa) wherein A is hydrogen and R is lower alkyl are
prepared from compound of formula (XII) by treatment with an alcoholic
solution of the appropriate alkali metal alkoxide such as sodium methoxide
in methanol at room temperature or with mild heating.
Various compounds of formula (XIV) may be prepared from compound of formula
(XIII). For example, compound of formula (XIVc) wherein A is acetyl is
prepared by treating compound of formula (XIII) with sodium azide in a
solvent such as ethanol:water, dimethylformamide, hexamethylphosphoramide
and the like. The reactants are heated for two to 24 hours at 80.degree.
to 200.degree. C. Compound of formula (XIVd), wherein A is hydrogen, are
prepared by hydrogenating compound of formula (XIVc) using, for example, a
palladium on charcoal catalyst.
Compound of formula (XIII) is converted to compound of formula (XIVe)
wherein A is hydrogen by heating compound of formula (XIII) and ammonia
dissolved in methanol in a bomb for 16 to 24 hours at 85.degree. to
110.degree. C. The above compound may be further ammoniated by heating
compound of formula (XIVe) dissolved in liquid ammonia in a bomb for 24 to
48 hours at 110.degree. to 150.degree. C. to form compound of formula
(XIVd) wherein A is hydrogen.
Another method of preparing compound of formula (XIVd) is by treating
compound of formula (XIVe) with hydrazine and then with a cold solution of
sodium nitrite to form compound of formula (XIVf) wherein A is hydrogen,
which in turn is hydrogenated to the compound of formula (XIVd) using, for
example, a palladium on charcoal catalyst.
The amino groups of compounds of formula (XIV) wherein R.sup.3 and/or
R.sup.6 is amino may be alkylated to the secondary or tertiary amines by
treatment with an alkyl halide such as methyl iodide. A preferred method
for preparing the above alkylated amino compounds is by reacting a
compound of formula (XIII) or (XIVe) with an alkyl or dialkyl amine.
Compounds of formula (IXa) wherein R.sup.8 is other than methyl may be
prepared by protecting the hydroxy groups of compound of formula (IX) with
a trityl protecting agent as defined infra, deacetylating the amino
nitrogen, reacting the deacetylated compound with the appropriate acid
chloride and removing the protecting groups with glacial acetic
acid:water.
Those compounds of formula (XIV) wherein A is acetyl may be hydrolyzed by
methods well known in the art such as by acidic or basic hydrolysis.
Compounds of formulas (XIVg) and (XIVh) may be prepared by the
hydrogenation of compounds of formulas (XII) and (XIVe) respectively using
a hydrogenation catalyst such as palladium in the presence of a base such
as magnesium dioxide.
Compound of formula (XIVi) wherein A is hydrogen is prepared by reacting
compound of formula (XIVh) with sodium nitrite in acetic acid to form the
6-keto compound which in turn is chlorinated with a chlorinating agent
such as phosphoryl chloride, phosphorous pentachloride and the like by
methods well known in the art. The 6-chloro intermediate is treated with
thiourea as described above.
Compounds of formula (XIVj) may be prepared, for example, by reacting
compound of formula (XIVe) with methanolic hydrogen sulfide-ammonium
carbonate as described in J. Org. Chem., 39(9):1256, 1974 or with sodium
mercaptide in dimethylformamide as described in J. Med. Chem.,
16(12):1381, 1973.
Compounds of formula (XIV) wherein R.sup.3 or R.sup.6 is thio may be
alkylated with an alkyl halide such as an alkyl iodide in a solvent such
as an alkanol at room temperature.
The following compounds of formula (XIV) wherein A is hydrogen, for
example, may be prepared by one or a combination of the methods discussed
above:
2-amino-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-methylamino-6-ethoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-amino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p.
155.degree.-157.degree. C.;
2-n-butylamino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-amino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl) purine;
2-dimethylamino-6-methylthio-9-(1,3-dihydroxy-2propoxymethyl)purine;
2,6-diazido-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p.
174.degree.-180.degree. C.;
2-methylamino-6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-amino-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2,6-di(methylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;
6-chloro-2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p.
197.5.degree.-198.5.degree. C.;
2-chloro-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-azido-6-ethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine
2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
2-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
6-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;
6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;
6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine; and
6-amino-2-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine.
Diesters of formula (I) may be prepared by esterification methods well
known in the art. For example, diesters of formula (I) wherein R.sup.7 is
lower alkyl may be prepared by reacting compounds of formula (X) and (XIV)
wherein A is hydrogen with an excess of the appropriate acid anhydride,
either neat or in a solvent such as dimethylformamide, dimethylacetamide,
N-methylpyrrolidine and the like. The reactants are stirred for one to
five days, preferably for two to three days at 0.degree. to 50.degree. C.,
preferably at room temperature in the presence of a catalyst, e.g.,
4-dimethylaminopyridine. Compounds of formula (X) or (XIV) and the acid
anhydride are in a molar ratio of approximately 1:10-100.
The acid anhydrides are readily available or if not readily available may
be prepared by methods well known in the art such as by heating the acid
in the presence of acetic anhydride or acetyl chloride.
The diesters of formula (I) wherein R.sup.7 is hydrogen may be prepared by
the above described method using the mixed anhydride of formic acid and
acetic acid, which may be prepared by reacting formic acid with acetic
anhydride, neat, at 0.degree. to 40.degree. C.
Another method for preparing the diesters of formula (I) for all values of
R.sup.7 is by first treating compound of formula (XI) or (XIV) wherein A
is acetyl and R.sup.3 and/or R.sup.6 is amino with a trityl protecting
agent such as triphenylmethyl chloride (trityl chloride),
4-methoxyphenyldiphenylmethyl chloride (mono-methoxytritylchloride) and
the like. The trityl protecting agents are readily available from, i.a.,
Aldrich Chemical Co.. The reactants in a solvent such as
dimethylformamide, pyridine, and the like with a catalyst e.g.,
4-dimethylpyridine are heated at 40.degree. to 70.degree. C., preferably
at 45.degree. to 60.degree. C. for 8 to 24 hours, preferably for 12 to 18
hours. The amino protected compound is isolated by conventional means such
as crystallization and the acetate groups are hydrolyzed with a base, such
as an alkali metal hydroxide, e.g., sodium hydroxide and potassium
hydroxide, or with ammonium hydroxide. The dihydroxy compound and a
catalyst such as 4-dimethylaminopyridine in pyridine is added dropwise to
the appropriate acid chloride either neat or in a solvent such as
methylene chloride, dichloroethane and the like. The reactants are stirred
at room temperature for 10 to 24 hours, preferably from 12 to 18 hours.
The product is isolated by methods well known in the art such as
chromatography. The amino protective groups are removed by treatment with
an organic acid such as glacial acetic acid, trifluoroacetic acid and the
like with heating from 60.degree. to 100.degree. C., preferably from
60.degree. to 80.degree. C. for one to twelve hours, preferably from one
to five hours. The product is isolated by chromatography or
crystallization.
The amino group(s) of the above described compound of formulas (XI) and
(XIV) may also be protected by reacting the compounds with the acetal of
N,N-dimethyl formamide available from, i.a., Aldrich Chemical Co. and then
proceeding as discussed above.
The acid chlorides are readily available or if not readily available may be
prepared by reacting the appropriate acid with a chlorinating agent such
as phosphorus trichloride, phosphorus pentachloride, or thionyl chloride
under reaction conditions well known in the art.
Diesters of formula (I) wherein R.sup.3 is amino, R.sup.5 together with
R.sup.6 is keto and R.sup.4 is hydrogen and R.sup.7 is alkyl of seven to
nineteen carbon atoms, alkenyl of seven to nineteen carbon atoms,
2-methyl-2-propyl, 1-adamantyl or phenyl may also be prepared by
esterifying with the appropriate acid chloride. The acid chloride
dissolved in a solvent such as methylene chloride, dichloroethane and the
like is added to compound of formula (IX) dissolved in a solvent such as
pyridine, lutidines and the like. The reactants are stirred for 9 to 24
hours, preferably for 16 to 24 hours at 15.degree. to 50.degree. C.,
preferably at room temperature. The amino group is deacetylated by
treatment with an alcoholic solution of a base such as a methanol solution
of ammonium hydroxide.
Another method for preparing diesters of formula (I) wherein R.sup.7 is
alkyl of seven to nineteen carbon atoms is by reacting compounds of
formulas (X) or (XIV) wherein A is hydrogen with the condensation product
of dicyclohexylcarbodiimide, available from Aldrich Chemical Co., and the
appropriate carboxylic acid. The carboxylic acid in a molar excess of
dicyclohexylcarbodiimide is added to the above compounds dissolved in a
solvent such as dimethylformamide, dimethylacetamide and the like. The
solution is stirred with heating from 35.degree. to 75.degree. C.,
preferably from 40.degree. to 60.degree. C. for 16 to 72 hours, preferably
for 24 to 60 hours. The diesters of formula (I) are isolated by
precipitation.
Diesters and monoesters of formula (I) wherein R.sup.7 is an hydroxyalkyl
are prepared by first protecting the hydroxy group of the hydroxy acid
with a benzyl group, reacting the protected acid with a trityl protected
compound of formula (X) or (XIV), as described infra, wherein A is
hydrogen and removing the benzyl group by catalytic hydrogenation followed
by removal of the trityl group(s) as discussed above.
The monoester of formula (I) may be prepared by reacting compounds of
formula (X) or (XIV) wherein A is hydrogen with a trityl protective group
as defined supra. The protective group reacts with the amino nitrogen if
present and one hydroxy group. The unprotected hydroxy group is esterified
using an acid chloride by the method described supra. The protective
groups are removed as described herein above.
The following specific description is given to enable those skilled in the
art to more clearly understand and practice the invention. It should not
be considered as a limitation upon the scope of the invention but merely
as being illustrative and representative thereof.
PREPARATION I
Preparation of 1,3-Di-O-benzylglycerol
Sodium hydride (100 g (50% dispersion in mineral oil), 2.08 mol) was washed
twice with 1 1 of hexane then dried under nitrogen. Dry dimethylformamide
(1.5 1) was added. Benzyl alcohol (400 ml) was then added at such a rate
to keep the temperature below 50.degree. C. The addition took 2 hours.
Epichlorohydrin (92.5 g, 1 mol) was then added dropwise over 0.5 hour with
ice cooling in order to keep the temperature below 40.degree. C. The
solution was next stirred for 16 hours at 21.degree. C. then for 2.5 hours
at 50.degree. C. The dimethylformamide was then removed by evaporation at
reduced pressure. The oily residue was dissolved in 2.5 1 diethyl ether.
The organic solution was washed with 2 l of water, 2 l of 2% hydrochloric
acid, 2 l of 1% sodium bicarbonate, and 1 l of brine, dried over sodium
sulfate, and concentrated to a brown oil. Distillation gave 147.8 g of
1,3-di-O-benzylglycerol (bp 170.degree.-180.degree. C./1 torr).
PREPARATION II
Preparation of 1,3-Di-O-benzyl-2-O-chloromethylglycerol
Dry hydrogen chloride gas was bubbled for 1.5 hours into a solution of
1,3-di-O-benzylglycerol from Preparation I (15 g, 55 mmol) and
paraformaldehyde (3.3 g, 110 mmol) in 175 ml of 1,2-dichloroethane at
0.degree. C. The solution was then stored in a stoppered flask for 21
hours at 4.degree. C. Next, the solution was dried over magnesium sulfate
with warming to 21.degree. C. then filtered and concentrated to give 17.5
g of 1,3-di-O-benzyl-2-O-chloromethylglycerol.
PREPARATION III
Preparation of 2-O-Acetoxymethyl-1,3-di-O-benzylglycerol
To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol from Preparation
II (17.5 g, 55 mmol) in 400 ml of dimethlyformamide at 0.degree. C. under
a drying tube was added sodium acetate (6 g). The solution was then warmed
to 21.degree. C. and magnetically stirred for 15 hours. The solvent was
removed by evaporation at reduced pressure and the oily residue dissolved
in 1 pound of diethylether. The ether solution was washed once with 750 ml
of water, two times with 250 ml of water, and once with 250 ml of brine,
dried over sodium sulfate and concentrated to give 19 g of
2-O-acetoxymethyl-1,3-di-O-benzylglycerol as an oil.
PREPARATION IV
Preparation of N.sup.2,9-Diacetylguanine
Guanine (20 g, 0.132 mol) was combined with 300 ml of acetic anhydride and
the mixture heated at reflux for 16 hours. The mixture was cooled and the
excess acetic anhydride removed by evaporation at reduced pressure. The
residue was recrystallized from dimethyl sulfoxide to give 25.6 g of
N.sup.2,9-diacetylguanine.
PREPARATION V
A. Preparation of N.sup.2
-Acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine
N.sup.2,9-Diacetylguanine from Preparation IV (15.61 g, 66 mmol),
2-O-acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (19 g, 55
mmol), and bis(p-nitrophenyl)phosphate (0.5 g) were stirred together with
150 ml of diethylether. The solvent was removed by evaporation and the
residue heated in a 175.degree. C. oil bath for 1.5 hours under a stream
of nitrogen. Column chromatography eluting with 1:9 methanol/methylene
chloride followed by recrystallization from ethyl acetate afforded 4.76 g
of N.sup.2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine, mp
145.degree.-146.degree. C.
B. Preparation of N.sup.2 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine
To a solution of N.sup.2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine
(4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added
20% palladium hydroxide on carbon as a slurry in 10 ml of water. The
mixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogen for
38 hours then filtered through celite and concentrated to a white solid.
Recrystallization from methanol/ethyl acetate gave 1.4 g of N.sup.2
-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp
205.degree.-208.degree. C.
The mother liquor was further reduced with 10% palladium on carbon (1 g) in
150 ml of methanol plus 50 ml of water at 60 psi for 47 hours. The total
yield of N.sup.2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine was 2.11
g.
C. Preparation of 9-(1,3-Dihydroxy-2-propoxymethyl)guanine
N.sup.2 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4
mmol) was stirred with 50 ml of methanolic ammonia solution (methanol
saturated with ammonia at 0.degree. C.) for 17 hours at 21.degree. C. The
solution was concentrated to a white solid and the residue recrystallized
from water or methanol to give 582.3 mg of
9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 250.degree. C.
EXAMPLE 1
9-(1,3-Diacetyloxy-2-propoxymethyl)guanine
(Compound Wherein R.sup.1 and R.sup.2 are Acetyl, R.sup.3 is Amino, R.sup.4
is Hydrogen and R.sup.5 and R.sup.6 are Keto)
A mixture of 3.00 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 300 mg of
4-dimethylaminopyridine, and 100 ml of acetic anhydride was vigorously
stirred for 3 days at room temperature. The acetic anhydride was removed
by evaporation at reduced pressure and the residue recrystallized from
methanol to give 3.62 g of 9-(1,3-diacetyloxy-2-propoxymethyl)guanine,
m.p. 237.degree.-239.degree..
EXAMPLE 2
9-(1,3-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine
(Compound Wherein R.sup.1 and R.sup.2 are 2,2-dimethylpropanoyl, R.sup.3 is
Amino, R.sup.4 is Hydrogen, and R.sup.5 and R.sup.6 are Keto)
A mixture of 1.306 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 150 mg of
4-dimethylaminopyridine, and 50 ml of 2,2-dimethylpropanoic acid anhydride
and dry dimethylformamide (75 ml) was vigorously stirred for 2 days. The
dimethylformamide was removed by evaporation at reduced pressure, and 200
ml of ethyl ether were added to the residue. After cooling to 0.degree.
C., the precipitate was isolated by filtration and recrystallized from
methanol to give 1.83 g of
9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine, m.p.
230.degree.-232.degree..
Similarly, using the procedure in Example 1 or 2, substituting the
appropriate acid anhydride for acetic anhydride or 2,2-dimethylpropanoic
acid anhydride and using compound of Formula (X) or the appropriate
compound of formula (XIV) wherein A is hydrogen the following compounds,
for example, are prepared:
2-amino-6-methoxy-9-(1,3-diacetyloxy-2-propoxymethyl)purine;
2-methylamino-6-ethoxy-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;
2-amino-6-thio-9-(1,3-di-acetyloxy-2-propoxymethyl)purine, m.p.
235.degree.-236.5.degree. C.;
2-n-butylamino-6-thio-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;
2-amino-6-methylthio-9-[1,3-di-2-methylpropanoyloxy)-2-propoxymethyl]purine
2-dimethylamino-6-methylthio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxy
methyl]purine;
2,6-diazido-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;
2,6-diamino-9-(1,3-diacetyloxy-2-propoxymethyl)purine;
2-methylamino-6-amino-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;
2-amino-6-methylamino-9-(1,3-di-n-butanoyloxy-2propoxymethyl)purine;
2,6-di(methylamino)-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]purine
;
6-chloro-2-amino-9-[1,3-diacetyloxy-2-propoxymethyl]purine, m.p.
122.degree.-123.degree. C.;
2-chloro-6-methylamino-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;
2-azido-6-ethylamino-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;
2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;
2-methylamino-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;
2-dimethylamino-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)purine;
6-amino-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]purine;
6-methylamino-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;
6-dimethylamino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine
;
6-thio-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;
6-methylthio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;
9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine, m.p. 191.degree.-193.degree.
C.;
9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine, m.p.
199.degree.-201.degree. C.;
9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]guanine;
9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine, m.p.
193.degree.-198.degree. C.;
9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine, m.p.
179.degree.-181.degree. C.;
9-[1,3-di-(4-methylpentanoyloxy)-2-propoxymethyl]guanine, m.p.
185.5.degree.-186.5.degree. C.;
9-(1,3-di-methoxyacetyloxy-2-propoxymethyl)guanine, m.p.
183.degree.-185.degree. C.; and
9-[1,3-di-(3-carboxypropanoyoxy)-2-propoxymethyl]guanine, m.p.
140.degree.-144.degree. C.
EXAMPLE 3
9-(1,3-Di-n-hexadecanoyloxy-2-propoxymethyl)guanine
To 50 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in 5 ml of
N,N-dimethylformamide were added 290 mg dicyclohexycarbodiimide and 300 mg
of n-hexadecanoic acid and the solution was stirred at 50.degree. C. for
50 hours. The compound was then precipitated in ice water. The water was
extracted with methylene chloride (3.times.). The combined methylene
chloride extracts were concentrated, then purified on preparative silica
gel plates developed in 1:9 methanol:methylene chloride to yield 140 mg
9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine, m.p.
150.degree.-154.degree. C.
Similarly, proceeding as in the above example, substituting the appropriate
carboxylic acid for n-hexadecanoic acid and using compound of formula (X)
or compounds of formula (XIV) wherein A is hydrogen, the following
compounds, for example, are prepared:
2-amino-6-methoxy-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)-purine;
2-amino-6-chloro-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;
2-amino-6-thio-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;
2-n-butylamino-6-thio-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;
2-amino-6-methylthio-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;
2-dimethylamino-6-methylthio-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)pu
rine;
2,6-diazido-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;
2,6-diamino-9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)purine;
2-methylamino-6-amino-9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)purine;
2-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;
2,6-di(methylamino)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;
2-chloro-6-amino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;
2-chloro-6-methylamino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;
2-azido-6-ethylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;
6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;
2-methylamino-9-(1,3-n-eicosanoyloxy-2-propoxymethyl)purine;
2-dimethylamino-9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)purine;
2-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;
6-methylamino-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;
6-dimethylamino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;
6-thio-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;
6-methylthio-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;
9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p.
165.degree.-166.degree. C.;
9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine, m.p.
158.degree.-160.degree. C.;
9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine, m.p.
162.degree.-164.degree. C.;
9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine, m.p.
137.degree.-140.degree. C.;
9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine; and
9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine.
EXAMPLE 4
A. N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine
A solution of 3.3 g of 9-(1,3-diacetoxy-2-propoxymethyl)guanine, 7.0 g of
4-methoxyphenyldiphenylmethyl chloride, 7.0 ml of triethylamine and 300 mg
of 4-dimethylaminopyridine in 50 ml of dry dimethylformamide was heated
with magnetic stirring at 50.degree. C. for 15 hours. Methanol (5 ml) was
added. The solution was then concentrated at reduced pressure to a brown
oil which was chromatographed over silica gel eluting with 1:12
methanol:methylene chloride to give an oil. The oil was crystallized from
ethyl acetate:hexane to give 5.42 g of N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine,
m.p. 139.degree.-141.degree..
Triphenylmethyl chloride may be substituted for
4-methoxyphenyldiphenylmethyl chloride in part A above to prepare the
corresponding triphenylmethyl protected compounds.
Similarly proceeding as above in Part A, substituting the appropriate
compound of formula (XIV) wherein A is acetyl, the following compounds,
for example, are prepared:
2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-diacetyloxy-2-propo
xymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-diacetyloxy-2-propoxym
ethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-diacetyloxy-2-pr
opoxymethyl)purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymet
hyl)purine;
2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-p
ropoxymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)p
urine;
6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propox
ymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)p
urine; and
6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)p
urine.
B. N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)quanine
A solution of 4.0 g of N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine
in 100 ml of methanol plus 20 ml of concentrated ammonium hydroxide was
magnetically stirred at 22.degree. C. for 16 hours then at 50.degree. C.
for 2.5 hours. An additional 10 ml of ammonium hydroxide were then added
and the solution stirred another 2.5 hours at 50.degree. C. Next, the
solution was concentrated at reduced pressure and the residual solid
recrystallized from methanol:ethyl acetate to give 3.5 g of N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine,
m.p. 148.degree.-151.degree. C.
Similarly proceeding as above in Part B the compounds prepared in Part A
may be hydrolyzed to the following compounds:
2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-dihydroxy-2-propoxy
methyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-dihydroxy-2-propoxymet
hyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-dihydroxy-2-prop
oxymethyl)purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethy
l)purine;
2-methylamino-6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-
propoxymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)pur
ine;
6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxym
ethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)pur
ine; and
6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)pur
ine.
C. N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)g
uanine
To a magnetically stirred solution of 1.05 g of N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine
and 25 mg of 4-dimethylaminopyridine in 30 ml of dry pyridine was added
dropwise a solution of 1.2 g of n-octanoyl chloride in 10 ml of methylene
chloride. After 15 hour, 1.5 ml of water was added and the solution
concentrated at reduced pressure. The residue was chromatographed over
silica gel eluting with 1:9 methanol:methylene chloride to give a white
solid which was recrystallized from ethyl acetate:hexane to N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)g
uanine.
Similarly, proceeding as in Part C above, the compounds from Part B may be
esterified to the following compounds:
2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-di-n-butanoyloxy-2-
propoxymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-[1,3-di-(2,2-dimethylpropan
oyloxy)-2-propoxymethyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-di-n-octanoyloxy-2-pro
poxymethyl)-2-propoxymethyl)-purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-[1,3-di-(1-adamantylcarboxy
)-2-propoxymethyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-di-n-heptanoylox
y-2-propoxymethyl)purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-decanoyloxy-2-propo
xymethyl)purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octanoyloxy-2-propo
xymethyl)purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(2,2-dimethylpropanoy
loxy)-2-propoxymethyl]purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(1-adamantylcarboxy)-
2-propoxymethyl]-purine;
2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-tetradecan
oyloxy-2-propoxymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-methylamino-9-(1,3-di-n-hexadecano
yloxy-2-propoxymethyl)purine;
6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octadecanoyloxy
-2-propoxymethyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octanoyloxy-2-propoxymet
hyl)purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(2,2-dimethylpropanoyloxy)
-2-propoxymethyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(1-adamantylcarboxy)-2-pro
poxymethyl]purine;
6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-dodecanoyloxy-2-propoxym
ethyl)purine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dipropanoyloxy-2-propoxymethyl)gua
nine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)g
uanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-(2-methylpropanoyloxy)-2-propox
ymethyl)guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)
guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-pr
opoxymethyl)guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)g
uanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)
guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)g
uanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl
)guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-tetradecanoyloxy-2-propoxymet
hyl)guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-hexadecanoyloxy-2-propoxymeth
yl)guanine clear oil;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octadecanoyloxy-2-propoxymeth
yl)guanine;
N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl
)guanine; and
N.sup.2
-(4-methoxyphenyldiphenyl)-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]
guanine; m.p. 201.degree.-203.degree. C.;
N.sup.2
-(4-methoxyphenyldiphenyl)-9-[1,3-di-(benzyloxyacetyloxy)-2-propoxymethyl]
guanine;
N.sup.2
-(4-methoxyphenyldiphenyl)-9-[1,3-di-(3-benzyloxypropanoyloxy)-2-propoxyme
thyl]guanine; and
N.sup.2
-(4-methoxyphenyldiphenyl)-9-[1,3-di-(4-benzyloxybutanoyloxy)-2-propoxymet
hyl]guanine.
D. 9-(1,3-Di-n-octanoyloxy-2-propoxymethyl)guanine
A solution of 0.969 g of N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)g
uanine in 40 ml of glacial acetic acid plus 10 ml of water was stirred at
75.degree. C. for 3 hours. The solution was then concentrated and the
residue chromatographed over silica gel eluting with 1:15
methanol:methylene chloride to give a white solid. The product was
recrystallized from methanol to afford 0.385 g of
9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p.
165.degree.-166.degree. C.
Similarly, proceeding as in Part D of the above example, using the
compounds of Part C the following compounds may be prepared:
2-amino-6-methoxy-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)purine;
2-amino-6-thio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;
2-amino-6-thio-9-[1,3-di-n-octanoyloxy-2-propoxymethyl]purine;
2-amino-6-thio-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;
2-amino-6-methylthio-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)purine;
2,6-di-amino-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;
2,6-di-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;
2,6-diamino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;
2,6-di-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;
2-methylamino-6-amino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;
2-amino-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;
2-chloro-6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;
2-amino-9-(1,3-di-octanoyloxy-2-propoxymethyl)purine;
2-amino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;
2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;
6-amino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;
9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine m.p 191.degree.-193.degree.
C.;
9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine m.p.
199.degree.-201.degree. C.;
9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]guanine;
9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine m.p.
193.degree.-198.degree. C.;
9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine m.p.
230.degree.-232.degree. C.;
9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine m.p.
179.degree.-181.degree. C.;
9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine m.p.
158.degree.-160.degree. C.;
9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine m.p.
162.degree.-164.degree. C.;
9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine
137.degree.-140.degree. C.;
9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine m.p.
150.degree.-154.degree. C.;
9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine;
9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]guanine m.p.
283.degree.-285.degree. C.;
9-[1,3-di-(2-butenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(9-dodecenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(cis-9-hexadecenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(cis-9-octadecenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(9,12-octadecadienoyloxy)-2-propoxymethyl]guanine; and
9-[1,3-di-(9,12,15-octadecatrienoyloxy)-2-propoxymethyl]guanine.
Similarly, catalytically removing the benzyl group and then proceeding as
in Part D of the above example the following compounds, for example, are
prepared:
9-[1,3-di-(hydroxyacetyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(3-hydroxypropanoyloxy)-2-propoxymethyl]guanine; and
9-[1,3-di-(4-hydroxybutanoyloxy)-2-propoxymethyl]guanine.
EXAMPLE 5
To 0.26 g of N.sup.2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine from
preparation V, Part B and 10 mg of 4-dimethylaminopyridine in a solution
of 7 ml of pyridine was added 0.764g of adamantanecarboxylic acid chloride
as a solution in 3 ml of methylene chloride. The solution was magnetically
stirred for 18 hours at 21.degree. C. then 1 ml of water was added. After
stirring an additional hour the solution was concentrated and the residue
was treated for 16 hours with 10 ml of methanol containing 1 ml of
concentrated ammonium hydroxide. The solution was concentrated and the
residue was triturated with methanol to give 0.277g of
9-[1,3-di(1-adamantylcarboxy)-2-propoxymethyl]guanine, m.p.
283.degree.-285.degree. C.
Similarly, proceeding as above using the appropriate acid chloride and the
appropriate compound of formula (IX) or (XIV) wherein A is hydrogen the
following compounds, for example, are prepared:
2-amino-6-methoxy-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]puri
ne;
2-amino-6-thio-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;
2-amino-6-methylthio-9(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;
2,6-diamino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;
2-methylamino-6-amino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;
2-amino-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;
2-chloro-6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;
2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;
6-amino-9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]purine;
9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine;
9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine;
9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine;
9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(9-dodecenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(cis-9-hexadecenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(cis-9-octadecenoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(9,12-octadecadienoyloxy)-2-propoxymethyl]guanine;
9-[1,3-di-(9,12,15-octadecatrienoyloxy)-2-propoxymethyl]guanine; and
9-(1,3-dibenzoyloxy-2-propoxymethyl)guanine, m.p. 242.degree.-243.degree.
C.
EXAMPLE 6
A. N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylme
thoxy)-2-propoxymethyl]guanine
To 2 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in N,N-dimethylformamide
(50 ml) was added 6.33 g of 4-methoxyphenyldiphenylmethyl chloride, 20 mg
of N,N-dimethylaminopyridine, and 10 ml of triethylamine. The reaction was
stirred at 50.degree.-60.degree. C. for 60 hours then precipitated in ice
water (900 ml). The precipitate was isolated by filtration and the product
recrystallized from ethanol. The slightly impure product was further
purified by column chromatography on silica gel eluting with 1:9
methanol:methylene chloride to yield 3.5 g N.sup.2
-(4-methoxyphenyldiphenylmethyl)-9-[1-hydroxy-3-(4-methoxy-phenyldiphenylm
ethoxy)-2-propoxymethyl]guanine after recrystallization from methanol, m.p.
159.degree.-161.degree. C.
Similarly, proceeding as in Part A above substituting the appropriate
compounds of formula (XIV) wherein A is hydrogen for
9-(1,3-dihydroxy-2-propoxymethyl)guanine and using the appropriate amount
of 4-methoxyphenyldiphenylmethyl chloride the following compounds for
example, are prepared:
2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-[1-hydroxy-3-(4-methoxyp
henyldiphenylmethoxy)-2-propoxymethyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-[1-hydroxy-3-(4-methoxyphen
yldiphenylmethoxy)-2-propoxymethyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-[1-hydroxy-3-(4-metho
xyphenyldiphenylmethoxy)-2-propoxymethyl]purine;
2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyl
diphenylmethoxy)-2-propoxymethyl]purine;
2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-meth
ylphenyldiphenylmethoxy)-2-propoxymethyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-6-methylamino-9-[1-hydroxy-3-(4-meth
oxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;
2-chloro-6-(4-methoxyphenyldiphenylmethylamino)-9[1-hydroxy-3-(4-methoxyphe
nyldiphenylmethoxy)-2-propoxy-methyl]purine;
2-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphe
nylmethoxy)-2-propoxymethyl]purine;
6-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphe
nylmethoxy)-2-propoxymethyl]purine;
2-methylamino-6-ethoxy-9-[1-hydroxy-3-(4-methoxyphenyl
diphenylmethoxy)-2-propoxymethyl]purine;
2-n-butylamino-6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-pro
poxymethyl]purine;
2-dimethylamino-6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy
)-2-propoxymethyl]purine;
2,6-diazido-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-pro
poxymethyl]purine;
2,6-di(methylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propo
xymethyl]purine;
2-chloro-6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-pr
opoxymethyl]purine;
2-azido-6-ethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-prop
oxymethyl]purine;
2-dimethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxyme
thyl]purine;
6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymeth
yl]purine;
6-dimethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)2-propoxymet
hyl]purine;
6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-propoxym
ethyl]purine; and
6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-pr
opoxymethyl]purine.
B. 9-(1-n-Hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine
To a stirred mixture of 3 g n-hexadecanoyl chloride in pyridine (50 ml) was
added 1.5 g of N.sup.2
-(4-methoxyphenylmethyl)-9-[hydroxy-3-(4-methoxyphenyldiphenylmethoxy-2-pr
opoxymethyl]guanine. The reaction was stirred 48 hours at
50.degree.-60.degree. C. and then precipitated in ice water (500 ml). The
resulting precipitate was treated with 80% acetic acid (aqueous) at
80.degree. C. for one hour. The acetic acid was evaporated under reduced
pressure and the residue chromatographed on a silica gel column eluting
with 1:9 methanol:methylene chloride to yield 0.45 g
9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine after
recrystallization from methanol m.p. 226.degree.-227.degree. C.
Similarly, proceeding as in Part B above substituting the appropriate acid
chloride for n-hexadecanoyl chloride the following compounds, for example,
are prepared:
2-amino-6-methoxy-9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)purine;
2-amino-6-thio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxy-methyl]p
urine;
2-amino-6-methylthio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymet
hyl]purine;
2,6-diamino-9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;
2-methylamino-6-amino-9-(1-n-pentanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-amino-6-methylamino-9-(1-n-hexanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-chloro-6-amino-9-(1-n-heptanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-amino-9-(1-n-octanoyloxy-3-hydroxy-2-propoxymethyl)purine;
6-amino-9-(1-n-decanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-methylamino-9-(1-n-dodecanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-n-butylamino-6-thio-9-(1-n-tetradecanoyloxy-3-hydroxy-2-propoxymethyl)pur
ine;
2-dimethylamino-6-methylamino-9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymet
hyl)purine;
2,6-diazido-9-(1-octadecanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2,6-di(methylamino)-9-(1-n-eicosanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-chloro-6-methylamino-9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)purine;
2-azido-6-ethylamino-9-(1-propanoyloxy-3-hydroxy-2-propoxymethyl)purine;
2-dimethylamino-9-(1-n-butanoyloxy-3-hydroxy-2-propoxymethyl)purine;
6-methylamino-9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;
6-dimethylamino-9-(1-n-pentanoyloxy-3-hydroxy-2-propoxymethyl)purine;
6-thio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;
6-methylthio-9-(1-n-hexanoyloxy-3-hydroxy-2-propoxymethyl)purine;
9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-butanoyloxy-3-hydroxy-2-propoxymethyl)guanine;
9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-(1-n-pentanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-hexanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-heptanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-octanoyloxy)-3-hydroxy-2-propoxymethyl)guanine m.p.
215.5.degree.-217.5.degree. C.;
9-(1-n-decanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-dodecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-tetradecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-octadecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-n-eicosanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-(1-methoxyacetyloxy)-3-hydroxy-2-propoxymethyl)guanine;
9-[1-(1-adamantylcarboxy)-3-hydroxy-2-propoxymethyl]guanine;
9-(1-benzoyloxy-3-hydroxy-2-propoxymethyl)guanine;
9-[1-(2-butenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(4-octenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(9-dodecenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(cis-9-hexadecenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(9,12-octadecadienoyloxy)-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(9,12,15-octadecatrionoyloxy)-3-hydroxy-2propoxymethyl]guanine;
9-[1-(2-butenoyloxy)-3-hydroxy-2-propoxymethyl]guanine; and
9-[1-(3-carboxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine m.p.
191.degree.-192.degree. C.
Similarly, catalytically removing the benyzl group and then proceeding as
above the following compounds, for example, are prepared:
9-(1-hydroxyacetyloxy-3-hydroxy-2-propoxymethyl]guanine;
9-[1-(3-hydroxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine; and
9-[1-(4-hydroxybutanoyloxy)-3-hydroxy-2-propoxymethyl]guanine.
EXAMPLE 7
A twofold stoichiometric excess of 3% hydrogen chloride in methanol is
added to a solution of 1.0 g. of
9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine in 20 ml methanol. Diethyl
ether is added until precipitation is complete. The product is filtered,
washed with ether, air dried and recrystallized to give
9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine hydrochloride.
In a similar manner, all compounds of Formula I in free base form may be
converted to the acid addition salts by treatment with the appropriate
acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid,
oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
and the like.
EXAMPLE 8
1.0 g of 9-(1,3-di-n-octanoyloxy-2 propoxymethyl)guanine HCl suspended in
50 ml of ether is stirred with a twofold stoichiometric excess of dilute
aqueous potassium carbonate solution until the salt is completely
dissolved. The organic layer is then separated, washed twice with water,
dried over maganesium sulfate and evaporated to yield
9-(1,3-di-n-octanoyloxy-2-propoxy methyl)guanine as the free base.
Alkali metal salts of mono and diesters of formula I, particularly where
R.sup.7 is 1-adamantyl or 2-methyl-2-propyl may be prepared according to
the following example.
EXAMPLE 9
The following example illustrates the preparation of representative
pharmaceutical formulations containing an active compound of Formula (I)
such as 9-[1,3-di-(2,2-dimethylpropanoyloxy-2-propoxymethyl]guanine.
______________________________________
A. Topical Formulation
______________________________________
Active compound 0.2-2 g
Span 60 2 g
Tween 60 2 g
Mineral oil 5 g
Petrolatum 10 g
Methyl paraben 0.15 g
Propyl paraben 0.05 g
BHA (butylated hydroxy anisole)
0.01 g
Water qs 100 ml
______________________________________
All of the above ingredients, except water, are combined and heated at
60.degree. C. with stirring. A sufficient quantity of water at 60.degree.
C. is then added with vigorous stirring to provide 100 g of the cream
formulation which is then cooled to room temperature.
The following formulation is useful for intraperitoneal and intramuscular
injection.
______________________________________
B. IP and IM Formulation
______________________________________
Active compound 0.5 g
Propylene glycol 20 g
Polyethylene glycol 20 g
Tween 80 1 g
0.9% Saline solution qs
100 ml
______________________________________
The active compound is dissolved in propylene glycol, polyethylene glycol
400 and Tween 80. A sufficient quantity of 0.9% saline solution is then
added with stirring to provide 100 ml of the I.P or I.M solution which is
filtered through a 0.2 micron membrane filter and packaged under sterile
conditions.
The following formulation is useful for intravenous injection.
______________________________________
C. I.V. Formulation
______________________________________
Active compound 0.1 g
Polysorbate 80 0.1 g
Propylene glycal or 3.0 g
polyethylene glycol 400
Water qs 100 ml
______________________________________
The active compound is added to a solution of polysorbate 80 and propylene
glycol or polyethylene glycol 400 in 20 ml of water and mixed. The
resulting solution is diluted with water to 100 ml and filtered through
the appropriate 0.2 micron membrane filter.
______________________________________
D. Tablet Formulation
Parts by weight
______________________________________
Active compound 200
Magnesium stearate 3
Starch 30
Lactose 116
PVP (polyvinylpyrrolidone)
3
______________________________________
The above ingredients are combined and granulated using methanol as the
solvent. The formulation is then dried and formed into tablets (containing
200 mg of active compound) with an appropriate tabletting machine.
EXAMPLE 10
The exceptional antiviral activity of the compound of the invention is
illustrated by the following assay procedures:
The Herpes simplex virus 2 strain G for infection is prepared in HEp-2 cell
cultures. Virus is adsorbed for 1 hour, fresh media is placed on the
cells, and they are incubated at 35.degree. C. until all cells were
infected. The cell suspension is frozen at -70.degree. C., thawed, and
centrifuged to remove cell debris. The supernatant fluid is aliquoted and
stored frozen at -70.degree. C. until use. A 10.sup.6.7 dilution of the
supernatant fluid producer a 50% cell culture infective dose (CCID.sub.50)
in HEp-2 cells and a 10.sup.3.7 dilution producer a 50% lethal challenge
(LC.sub.50) in mice.
Groups of 20 Swiss Webster female mice (15-17 gm), are challenged by
intraperitoneal route using 0.2 ml of EMEM containing 10 LC.sub.50 /mouse
of virus. Mice challenged with 10.sup.0.5 more or less virus than the 10
LD.sub.50 challenge serves as a virulence control to assure the model is
working properly.
Treatment with test compounds begins 6 hours post-challenge. The mice,
divided into groups of 20, are administered the compounds in saline s.c.
at 5 mg/kg, 10 mg/kg and 20 mg/kg. One group of 20 mice is used as a
control group and administered saline s.c. The treatment is repeated at
24, 48, 72 and 96 hours post-challenge.
Compounds of the instant invention show antiviral activity in the above
test.
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